TY - JOUR
T1 - Specific proteome changes in platelets from individuals with GATA1-, GFI1B-, and RUNX1-linked bleeding disorders
AU - van Bergen, M. G. J. M.
AU - Marneth, A. E.
AU - Hoogendijk, A. J.
AU - van Alphen, F. P. J.
AU - van den Akker, E.
AU - Laros-van Gorkom, B. A. P.
AU - Hoeks, M.
AU - Simons, A.
AU - de Munnik, S. A.
AU - Janssen, J. J. W. M.
AU - Martens, J. H. A.
AU - Jansen, J. H.
AU - Meijer, A. B.
AU - van der Reijden, B. A.
N1 - Funding Information: This work was supported by the Landsteiner Foundation for Blood Transfusion Research (project 1531). A.E.M. is sponsored by US Department of Defense Horizon Award W81XWH2010904. Publisher Copyright: © 2021 American Society of Hematology
PY - 2021/7/8
Y1 - 2021/7/8
N2 - Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.
AB - Mutations in the transcription factors GATA binding factor 1 (GATA1), growth factor independence 1B (GFI1B), and Runt-related transcription factor 1 (RUNX1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction resulting in a grayish appearance in blood smears. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from 11 individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1Q154Rfs, or RUNX1TD2-6 and 28 healthy controls were examined by label-free quantitative mass spectrometry. In total, 2875 platelet proteins were reliably quantified. Clustering analysis of more than 300 differentially expressed proteins revealed profound differences between cases and controls. Among cases, 44 of 143 significantly downregulated proteins were assigned to platelet function, hemostasis, and granule biology, in line with platelet dysfunction and bleedings. Remarkably, none of these proteins were significantly diminished in all affected cases. Similarly, no proteins were commonly overrepresented in all affected cases compared with controls. These data indicate that the studied transcription factor mutations alter platelet proteomes in distinct largely nonoverlapping manners. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.
UR - http://www.scopus.com/inward/record.url?scp=85109449873&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/blood.2020008118
DO - https://doi.org/10.1182/blood.2020008118
M3 - Article
C2 - 33690840
SN - 0006-4971
VL - 138
SP - 86
EP - 90
JO - Blood
JF - Blood
IS - 1
ER -